Cad . Saúd e Púb lic a, Rio de Jane iro , 14(Sup. 3):125-132, 1998
O rganochlorine exposure and breast
cancer risk in Colombian women
Expo siç ão a o rg ano c lo rad o s e risc o d e c ânc e r
d e mama e m mulhe re s c o lo mb ianas
1 Ce n t ro de Sa lu d Po b l a c i o n a l , In st i tu t o N acio n a l d e S alu d Pú bl ica d e M éx ico. Av. Un i v ersid ad 65 5, S an t a M arí a Ah u a c a t i t l á n , C . P. 6 2 5 0 8 , Cu e r n a va c a , M o re l o s ,M é x i c o. o l a y a @ i n s p 3 . i n s p . m x 2 Min isterio da Sa lu d d e Colo m bia, Su b d i recció n d e Acción es Priorit árias d e S al u d , Di recció n Ge n e ra l d e Prom oció n y Pre ve n c i ó n . Ca r re ra 13 no3 2 - 7 6 , Sa n t afé d e Bo g o t á ,C o l o m b i a . j ro d r i g u @ b o g o t a . m i n s a l u d . g ov. c o
3 División de Ep i d e m i o l o g i a , In st it u t o N a cio n al de Ca n c e rología d e Col om b ia . Ca lle 1 no9 - 5 5 ,
Sa n t af é d e Bo g o t á ,C o l o m b i a . e p i 5 0 1 @ i b m . n e t
4 Te k n o c rom a Ltda ., La b o ra t ori o y Con su l t oría Am b i e n t a l .
Ca ll e 22 bis no4 4 A - 1 5 , Ba r r i o Qu in t a Pa re d e s ,A .A .0 5 4 7 4 2 , Sa n t af é de Bo g o t á ,C o l o m b i a . t e k n o c ro @ l a t i n o. n e t . c o P. Ol a y a - C o n t re ra s 1 , 2 J . Ro d r í g u e z - Villa m i l 2 H . J . Po s s o - Va len cia 3 J . E. C o rt ez 4
Abstract An ep i d e m i o lo gi ca l st u d y w a s p erf o rm ed i n Sa n t a f é d e Bo g o t á , C o l o m b i a , w i t h a t o t a l o f 30 6 w o m en en ro l l e d , i n clu d i n g 153 i n cid en t BC ca ses a n d 153 a ge- m a t ch ed con t ro l s . T h e o b j e c t i v e o f t h i s st u d y w a s t o ev a l u a t e t h e a sso ci a t io n b et w e en BC ri sk a n d se ru m d i c h l o ro d i p h e n y l - d i c h l o roet h en e (DD E) leve l s . S o c i o d e m o g ra p h ic a n d re p ro d u c t i ve d at a , d i e t , a n d p a st ex p o s u re t o p est i ci d es w ere ob t a i n ed t h ro u gh a st ru ct u red q u est i o n n a i re . C h e m i c a l a n a lysis o f sa m p les w a s p erform ed by h igh reso lu t i o n ga s ch ro m a t o g ra p h y - E C D. Li k eli h ood of d e v elo p i n g BC by ex p o s u re t o t h ese su bst an ces w a s ev a lu a t ed t h rou gh odd s ra t ios (OR) a d ju st ed f o r : first -ch ild bre a s t - f e e d i n g , fa m ily BC h istory, body m a ss in dex (BM I), p a r i t y, a n d m en op a u sal s t a t u s . D at a a n a lysis w a s p erform ed by con d i t ion a l logi st ic re g ressio n t ech n i qu es. Ad ju st ed OR for ex p o s u re t o seru m DDE a n d BC su ggest s a n in crea se risk o f BC in t h e h igh er cat egory of DDE ex p o s u re (OR = 1.95; CI 1.10- 3.52). T h e t est for t re n d w a s n o t st a t ist ica lly sign ifi ca n t (p = 0.09). We con firm t h a t seru m DDE levels bear a p osit ive a sso cia t ion t o risk of BC a n d cou ld su p p o rt t h e a ssociat ion bet w een risk of BC an d bu rd en of D DE ex p o s u re .
Key words Brea st N e o p l a s m s ; En v i ro n m en t a l Ex p o s u re ; Pest ici d e Ex p o s u re ; Logi st i c Re g re s-s i o n ; Ca s-s e - C o n t rol St u d i e s-s
Resumo Em est u do ep id em ioló gico rea li za d o em Sa n t a Fé d e Bo g o t á ,C o l ô m b i a , 153 ca so s in ci-d en t es ci-d e câ n cer ci-d e m a m a (CM ) f o ra m com p a ra ci-d os com 153 co n t ro l e s , p a rea ci-d os p o r i ci-d a ci-d e. O o b j e t i v o d est e e st u d o f oi a v a l ia r a a sso ci a çã o e n t re o risco d e CM e n í v eis séricos d o p est i ci d a DDT (DD E). D ad os re p ro d u t i vos e sócio-d em ográf icos, c a ract eríst icas d a d iet a e in form açã o so-b re ex p osiçã o p re g ressa a p est i cid a s fora m oso-bt id os p or m ei o de qu est ion á ri o. A a n áli se qu ím ica d e a m o st ra s d e sa n gu e fo i rea li z a d a a t ra v és d e cro m a t o g ra fia a ga z d e a lt a resolu çã o – ECD. A v e rossim elh an ça d e d esen vo l v er CM com o decorrên ci a de ex p osiçã o a est a s su bst ân cia s foi a v a-liad a a t rav és d e od d s r a t i o s( O R ) , ob t ida s p or t écn ica s d e re g ressão logíst ica con dicio n al, a j u s t a-d as p ara am a m en t a çã o a-d o p rim ogên it o, h ist ória fa m iliar a-d e CM , ín a-d ice a-d e m a ssa co rp ora l ,p a r i-d a i-d e e p resen ça i-d e m en op a u sa. As OR a ju st a i-da s su gerem u m risco au m en t a i-d o i-d e CM n o estra t o d e m a ior ex p o sição a DDE (OR = 1,95; C . I . 1 , 1 0 - 3 , 5 2 ) ,e m b o ra o t este d e t en d ên cia fosse esta t ist i-ca m en t e n ã o sign ifii-ca t iv o (p = 0,09). Os resu lt a d o s en con t ra d os con st a t a ra m qu e os n í v eis séri-cos d e D DE est ã o p osit iva m en t e a ssocia dos co m o risco de CM , e p o d eria m a p oia r a h ip ót ese des-t a a ssocia çã o.
I n t ro d u c t i o n
Bre as t ca n c e r (BC) is t h e m o st c o m m o n ca n -ce r a m o n g w om e n a n d is a gr owin g p ro b l e m ( Wo rld Can cer Re s e a rch Fo u n d a t i o n / A m e ri c a n In stitu te for Ca n ce r Re s e rach , 1997). In Co l o m -b ia it is t h e se con d le ad in g ca u se of ca n ce r- re-la t e d d e a t h s a m o n g wo m e n , a s it is fo r Am eri-ca n wom en (In stitu to Co lo m b ia n o Nacion al d e Ca n c e rolo gía, 1990). In h e rited m u tat io n s in th e B RCA1 o r BRCA2 ge n e s, in cre a sin g age, e a rly m e n a rc h e, la te m e n o p au se, n u llip a ri t y, p ri m i-p a rit y a fte r age 30, i-p e rso n a l or fam ily h isto ry o f BC, a n d p ossib ly h igh -fa t d iet are th e b e st d oc-u m en t ed risk factors to d a te. Mo rtalit y ra tes a re fa llin g a m o n g wh it e wo m e n , e s p e cially t h o s e u n d e r 65 yea rs o f a ge, eve n in Sou t h Am e ri c a n c o u n t rie s (Wo rld Can cer Re s e a rch Fo u n d at i o n / A m e r ica n In stit u t e fo r Ca n cer Re s e rach , 1997). It h as b ee n su gge ste d th a t som e ch em ica l co n -t a m in a n -t s su ch a s DDT- re la -t e d c om p o u n d s , which p ossess estro gen ic a ctivity (as xen ob iotic e s t ro ge n s), co u ld b e ass o cia t e d wit h t h e in c i-d e n ce o f t h is t yp e o f t u m o r ( Wo lff & We s t o n , 1997; Wo lff et a l., 1993; Krie ge r et al., 1994). T h e a l t e rn a t i ve e st ra d iol p a t h wa y yie ld s t h e ge n o -t oxic 16 alph a-h yd rox ye s -t ron e (16 alph a-O H E 1 ) , w h ic h e n h a n ce s b re a st ce ll gro wt h , in c re a s e s u n sch ed u led DNA syn th esis, a n d o n co gen e an d v i r u s exp ression an d in crea ses an ch ora g e - i n d e-p en d en t growth ( Wolff &ame-p; We ston , 1997; Da vis et a l., 1993). Ep id e m io lo gic a l s t u d ie s co m p ar i n g e x p o s u re t o DD T a n d BC a re in co n c lu sive ( Wo lff e t al., 1993; Krie ge r e t a l., 1994; Hu n t e r e t a l., 1997; Va n’t Ve e r e t a l., 1997; De w ailly e t a l., 1994; Lóp ez - Ca r rillo e t al., 1997), p ro b a b l y b e ca u se th e y h a ve b e e n p e rf o r m e d in p o p u la-tion s am o n g wh o m DDT u se h a s b ee n p ro h i b i t-ed for over 20 yea rs ( Wo lff et a l., 1993; Krie ger et a l., 1994; Hu n t e r e t a l., 1997; Va n ’t Ve e r e t a l., 1997; De wa illy e t a l., 1994). In Co lo m b ia D DT wa s u s e d u n t il 1986 in a gri c u l t u re, p ri n c i p a l l y fo r t h e p ro d u ct io n o f c o t t on , ri c e , a n d flowe r s fo r e xp o rt a n d h a s b e e n re s t r ict e d fo r ve c t o r c o n t ro l sin ce 1994 ( Wo lff et a l., 1993; Krie ge r et a l., 1994; H u n t e r e t a l., 1997; Va n’t Ve e r e t a l., 1997; De w a illy e t a l., 1994). So m e st u d ie s in Colo m b ia h ave sh own th e p resen ce of DDT an d D DE le ve ls in fis h a n d a n im a l t is su e s, w a t e r, a n d so m e foo d s (Mi n i s t e r io d e Salu d d e Co -lo m b ia , 1992). In th is co n t e xt , an e va lu a t io n is n e e d e d o f t h e p ot e n t ial e ffe c t o f o rg a n o c h l o -rin e p est icid e s o n p o p u la t ion s with h igh e r ex-p o s u re le ve ls t h a n t h o se s t u d ie d t o d a t e. T h e a im o f the p rese n t stu d y was to assess the associa tion between BC an d DDE (d ich loro d i p h e n y l -d i c h l o ro e t h e n e ), a n o rg a n o c h l o r in e p e st ici-d e, in a grou p of Colom b ian wo m e n .
M aterials and methods
S u b j e c t s
A h o sp it a l c a se - co n t ro l s t u d y wa s ca r rie d o u t in Bogo t a , Co lo m b ia , fro m Ju ly 1995 to Fe b r u -a ry 1996. C-a se s in c lu d e d 164 h ist o lo gic -ally c o n f i r m e d in cid e n t BC p a t ie n t s id e n t ifie d in t h e m a in h o sp it a l o f t h e ca p it a l cit y (Co l o m -b ian Na tio n al Can ce r In stitu te ), an d th ose with n o clin ica l in d ica t ion o f d ist a n t m e t a st a se s a t d i s c h a rge we re in clu d e d . An a ge m at ch ed co n -t ro l (±2 ye a rs) wa s se le c-t e d fo r e a ch c a se fro m a sim ilar h o sp it al t h at p rovid e s ca re fo r n o n -ca n ce r p a t ie n t s fro m Sa n Ju a n d e Dio s: H o s p i-t a l Ou i-t - Pa i-t ie n i-t Se r vice s: (Ur o l o g y, O p h i-t h a l-m o l o g y, In t e rn a l Me d i c i n e, an d Ea r, No s e, an d T h ro a t De p a rt m e n t s). Fro m a t o t a l o f 328 p a -t ie n -t s in -te r v i e we d , ch em ical an a lysis of b lo od sa m ple s was ob ta in e d for 306 p a rt i c i p a n t s, an d t h e re su lt s a re p re s e n t e d in t h is p a p e r. T h re e q u e s t i o n n a i res we re u sed in the in terviews with p a rt icip an t s p rior to sign in g th e in fo rm ed co n sen t. Th e first q u estio n n a ire exp lored socioe co -n o m ic a -n d re p ro d u c t i ve ch a ra c t e ri s t i c s, fam ily an d p at ien t hea lth h istory, an d occu p a tion . T h e se co n d fo cuse d o n d iet , an d th e t h ird e xp lore d p rio r p esticid e re late d an d occu p at ion a l e xp o -s u re. Sam p le -size wa-s ca lcu la ted to d et ect twice t h e risk fo r t h e fa ct o rs t o b e e va lu a t e d , wit h a p owe r of 80% an d co n fid e n ce leve l of 95% wh e n su ch d iffe re n ces e xist ed (Bre s l ow & Da y, 1980).
Blood samples
A 10 m l b lo od sa m p le wa s o b t ain e d fro m e ach wo m an , usin g ste rile va c u t a i n e r s. We o b t a in ed t h e se r u m b y ce n t r ifu ga t ion a n d st o re d it in gla ss via ls (p re w a s h e d w it h h e xa n e ) co ve re d wit h a Te flo n ca p . Se ru m sp ecim e n s we re ke p t in fro zen st o rage a t t h e Nat io n a l On co lo gy In -stit u t e in Bo got a at -7oC d u rin g t h e st u d y p er i-od . Blo o d s a m p le s we re d ra wn p r io r t o a n y c h e m o t h e ra p h y in t h e ca se s.
Chemical analyses
Cad. Saúde Púb lic a, Rio de Jane iro , 14(Sup . 3):125-132, 1998 c h ro m a t o g ra p h y u n d e r st a n d a rd c on d it io n s
( Da le et al., 1996). Ch em ica l results we re re p o rt-ed o n th e b asis o f vo lu m e (n g/ m l o r p p b ). DDE d et e ct io n lim it wa s 0.10 p a rt p e r b illio n (p p b ). In ad d it io n , la b o ra t o ry p e rso n n el we re b lin d to t h e h ea lth y ve rsu sd isea se d st a tu s o f t h e sa m -p les, so as n ot to b ias m easu rem en t o f ex-p osu re.
St atistical analysis
Da t a a n a lysis wa s p e r f o rm e d u sin g STATA 5.0 s o f t w a re (Te xas U n i ve r sit y). Alt h o u gh ske we d d i s t rib u t ion s o f DDE re q u i re d lo gtra n s f o rm a -t ion s in d a -t a an alysis, re su l-t s a re p re se n -t e d o n t h e ir o r igin a l sc a le s. Ce n t e r- a d ju st e d m e a n s we re ca lcu late d for DDE a n d m a jo r risk fa cto rs for BC, a n d th e Wi l c oxon m a t ch ed -pa irs sign e d ra n ks t e st wa s u se d for n o n p a ra m e t ric c om -p a r iso n s o f m e d ia n co n c e n t ra t io n s a n d t h e m at ch ed te st fo r t h e m e a n co m p a ri s o n s. Od d s rat io (OR) was u se d as th e p rin cip al m easu re of a sso ciatio n . To id en tify p ote n tial co n fou n d e rs, m e a n le ve ls o f r is k fac t o rs fo r BC we re co m -p a re d a m o n g t e rt ile s o f DD E co n c e n tra t io n in c o n t rols: BMI (kg/ m2), p a ri t y, firstch ild b re a s t -fe e d in g (m o n t h s), cu m u la t ive b re a s t - f e e d i n g (m o n t h s), fam ily h ist o r y of BC, a n d so cio e c o -n o m ic co -n d it io -n s. OR a-n d 95% CI fo r BC we re o b t a in e d fr o m m u lt iva ria t e c o n d it io n a l lo gis-t ic re g re s s io n a n a lys is (m a xim u m like lih o o d ra t io t e st ) (Br e s l ow & Da y, 1980), m o d e lin g DD E firs t in t e r t ile s a n d a s a c o n t in u o u s va r i-a b l e , co m p i-a r in g r isk for s u b je c t s in t h e fir s t a n d la s t t e r t i l e. Te s t fo r t re n d w a s c o n d u c t e d t h ro u gh t h e e xac t t e st fo r t re n d (m o d ifie d Wi l c oxo n t e st fo r t re n d ), a n d we in clu d e d t h e con tin u ous DDE va riab le in th e satu ra ted m o d e l (p valu e fo r t re n d ). In t e ra ct io n t e r m s b e t we en DDE an d BMI, p a ri t y, cu m u lat ive b re a s t fe e d in g (m o n t h s), p rio r fa m ily BC, a n d ge o -g ra p h ic o r i-gin p rio r t o 15 ye a rs o f a -ge (r u ra l , p e riu rb a n , o r u rb an ) we re t este d , b u t n o n e a p p e a re d t o b e st a t istically sign ifica n t . O th e r a u -t h o r s h a ve a d ju s-t e d -t h e m o d e ls -t o so m e of th ese va ria b le s ( Wolff et a l., 1993; Krieger et a l., 1994; Hu n t e r e t a l., 1997; Va n’t Vee r et a l., 1997; De wa illy e t a l., 1994; Ló p e z - Ca r r illo e t a l., 1997), m akin g o u r resu lt s m o re co m p ara b l e.
R e s u l t s
Th e ca s e -c o n t ro l DDE a n a lysis in c lu d e d 153 wo m en with BC an d 153 h ea lt h y m a tch ed co n -t ro l s. Age o f wo m e n e n ro lle d in -t h e s-t u d y va r-ie d fro m 26 to 75 ye a r s, with a m e a n a ge o f 50. Ta b le 1 d e scr ib e s a d ju s t e d re p ro d u c t i ve r i s k s a sso cia te d wit h BC, an d risk fact o rs a sso ciat e d
wit h t h e e ve n t we re fo u n d t o b e n u llip a rit y a s c o m p a re d t o wo m e n wit h ove r t h re e c h ild re n , a ge a t fir st ch ild b ir t h (ove r 25 a s co m p are d t o u n d e r 20), a n d fa m ily h isto ry o f BC. Pro t e c t i ve fa ct o rs fo r BC in clu d e d first ch ild b re a s t f e e d -in g a n d cu m u la t ive b re a s t -fe e d -in g; t h e la t t e r p rovid e d 70% p ro te ction as co m p a re d t o t ho se t h a t h a d ch ild re n b u t h ad n o t b re a st -fe d (OR = 0.30; CI 0.14 0.64). We a lso fo u n d t h a t so cio e -co n om ic le vel d e te rm in es life styles a n d re p ro-d u c t i ve e ve n t s in w o m e n , b a se ro-d o n wh ich w e ca lcu la t e t h a t m id d le c la s s wo m e n p re s e n t a r isk o f BC 3.82 t im e s h igh e r t h a n lo w - i n c o m e wo m e n . BM I wa s a s so c iat e d wit h t h e d ise a se , b u t wa s n o t st a t ist ica lly sign ifica n t. Ea rly m e n a rch e wa s a sse ssed as a p o ssib le risk fact or fo r t h is n e o p la sm . Me a n a ge a t m en a rc h e wa s 13 ye ars an d t h e re wa s n o p o sit ive a sso ciat io n wit h BC in th e st u d y p o p u la t io n .
As fo r t h e q u e st io n n a ire in clu d in g in d ire c t e x p o s u re t o p e st icid e s, we fo u n d t h a t wo m e n re f e r r in g fre q u e n t (we e kly) p a s t u s e o f p e st i-c id e s/ in s e i-c t ii-cid e s h a d a BC r isk o f 1.88 (CI 0.90-3.55) a s c o m p a re d t o t h o s e u sin g su c h su b s t a n ce s ve ry ra re ly (fe w t im e s a ye ar ). Ris k for wom en u sin g in secticid e s m o n th ly to q u a r-t e r ly w a s 1.33 (CI 0.75- 2.36) a s co m p a re d r-t o t h o se u sin g t he m o n ly ve ry ra re l y. Th e m ost fre-q u e n t ly u se d in se ct icid e gr o u p wa s t h e c arb a-m a t e s, follo we d b y py re t h ro id s an d t h e n o rg a n o c h l o ri n e s , ge n e ra lly u se d in sid e t h e h o m e wit h ou t a n y kin d o f in d ivid u a l p ro t e c t io n (d a ta n o t sh own ). Su ch d a t a cou ld b e co n -s i d e re d -su rroga t e-s fo r o rg a n o c h l o rin e u -se.
Ta b le 2 sh ow s m e a n s er u m p e st icid e. To t a l p op u la tion m ean DDE wa s 2.90 p p b, an d m e an s e ru m p est icid e was h igh e r in case s (3.30 p p b ) a s co m p ar e d t o c on t ro ls (2.90 p p b ), re a c h i n g sta tistical sign ifican ce in t h e com p a rison of th e m e a n s t r a n s f o rm e d in t o n a t u ra l lo ga ri t h m s. Th e d ifferen ce in t h e m ed ian s b etween th e ca s-e s a n d co n t ro ls a ls o p r ovs-e d t o b s-e st a t is t ica lly sign ifica n t , a n d t h is a s so ciat io n was o n ly m a in t a in e d fo r p re m e n o p a u s a l wo m e n wit h t h e d a t a stra t ified fo r m e n o p a u sal sta t u s.
Th e fu n d a m e n t a l d iffe re n ce o f a 95% e xc e s s r is k fo r ca se s a s c o m p a re d t o co n t ro ls wa s fou n d in t h e fin a l ter t i l e, wh ere t h e h igh est le v-e ls a rv-e o b sv-e r vv-e d , v-e s p v-e cia lly a m o n g yo u n g v-e r wo m en . Th e asso cia t io n b e twee n DDE a n d BC in th is gro u p o f Colo m b ia n wom en wa s sim ilar with in strat a of a ge at b irt h of first ch ild , p ari t y, a n d h ist o r y o f b re a s t -fe e d in g, a s we ll a s ge o-g ra p h ic o rio-gin p r ior t o 15 yea rs o f a o-ge.
D i s c u s s i o n
D DT a n d m e t a b o lit e s h a ve b e e n c a lle d “e n -d o c rin e -d isr u p t e r s” b ecau se evi-d en ce su ggest s t h a t t h e y can d isru p t th e e n d ocrin e syste m a n d
c o n t rib u t e t o t h e d e ve lo p m e n t of BC ( Wo lff & We st o n , 1997; Wo lff e t a l., 1993; Da vis e t a l., 1993; Ma c La ch la n & Arn o ld , 1996; Alle n e t a l., 1997; Wolff & La n d r iga n , 1994; Ha n s e y, 1994). On e wa y DDT in flu e n ce s BC risk is b y in cre a s-in g th e p ro d u ctio n a n d circu la ts-in g b loo d le ve l s o f ce rt a in t yp e s o f e s t ro ge n s ( Wo lff & We s t o n , 1997; Da vis et a l., 1993; Allen e t a l., 1997; Wo l f f & La n d rigan , 1994). In th is sen se, DDT m a y act as a p ro m o te r of b re ast tu m o rs in d u ced b y o th er ca rcin oge n s ( Wo lff & We st on , 1997). Th e o b s e rva t io n t h a t D DT co u ld b e h a ve a s an e st ro gen p rovid ed a fra m e w o rk for t h e u n d e rst a n d -in g t h at ch em ica ls n o t sp e cifically d e sign e d t o h a ve h o r m o n a l ac t ivit y m a y in fa ct d is p la y it ( MacLa ch lan & Arn old , 1996). In t h is se n se, we
Tab le 1
Adjuste d O d ds Ratio s fo r the re p ro d uctive s variab le s and the b re ast c ance r risk in the c o lo mb ian wo me n.
Suspect ed fact or O R C I 9 5 % Value p5
Age at menarche (years)*
8 - 1 3 1 . 0 2 0 .50 - 2.14 0 . 4 0
1 4 - 1 5 1 . 4 2 0 .82 - 2.50 –
≥ 16 1 . 0 – –
P a r i t y* *
Ye s 2 . 3 4 1.1 - 5.44 0 . 0 0 1
N o 1 . 0 – –
Age at birt h first child*
≥ 25 3 . 1 1.2 1 - 3 .0 –
2 0 - 2 5 1 . 5 6 0.84 - 2.60 0 . 6 3 6
< 20 1 . 0 – –
B reast feeding at first child (months)*
1 3 - m a x 0 . 7 6 0 .30 - 1.90 –
1 - 1 2 0 . 6 0 0 .24 - 0.14 0 . 4 0
0 1 . 0 – –
H i s t o ry of lact at ion lact ation (mont hs)* *
≥ 24 0 . 6 3 0.3 0 - 1 .25 –
1 - 2 3 0 . 3 0 0.1 4 - 0 .64 0 . 0 0 1
0 1 . 0 – –
Familial breast cancer*
Ye s 8 . 0 2.0 - 34.0 –
N o 1 . 0 – –
Place of orig en bef ore 15 years*
A re a ru r a l 2 . 3 5 1.32 - 4.20 –
A re a sub urb an 3 . 0 1.16 - 7.22 –
A re a urb an 1 . 0 – –
Quet elet index (Kg/ m2)*
≥ 30 1 . 2 0 0 .9 1 - 3 .0 –
2 5 - 2 9 1 . 6 0 0.62 - 2.30 0 . 9 6
2 4 1 . 0 – –
M enopausal st at us
N o 1 . 0 – –
Ye s 0 . 6 2 0.2 2 - 1 .73 –
O R = O dd s ratio ; CI95% = c o nfid e nc e Inte rvals, p5= value fo r tre nd , n = 3 06.
Cad. Saúde Púb lic a, Rio de Jane iro , 14(Sup . 3):125-132, 1998 fo u n d a r isk a sso cia t io n b e twe e n BC a n d DDE
s e ru m le ve ls fo r h igh DD E b u rd e n (i.e., t h e h igh e st t e r t ile co m p a re d t o t h e lowe st ). We c o n f i rm t h at ser u m DDE le vels b e ar a p osit ive a s so c ia t io n with d u r a t io n of b re a s t - f e e d i n g , BMI, a n d a ge , as in p re vio u s st u d ie s ( Wo lff e t al., 1993; Kr ie ge r e t a l., 1994; H u n te r e t a l., 1997; Lóp ez Ca r rillo et a l., 1997). Th e sa m e au -th o rs c o n firm t h a t t h e lo n ge r t h e c u m u la t ive d u ra t io n o f b re as t -fe e d in g a n d in so m e ca se s
t h e gre at e r t h e wo m a n ’s p ar i t y, t h e lo we r t h e s e ru m p e st ic id e le ve l s. In t h e o p p o s it e d ire c -t io n , in c re a se d a ge a n d BMI we re a s so cia -t e d wit h gre a t e r a c cu m u la t ion o f DDE in s e r u m a n d a d ip o se t is su e (H u n t e r e t a l., 1997; Va n’t Ve e r e t a l., 1997; D e wa illy e t a l., 1994; Lóp ez -Ca r rillo et a l., 1997). With re g a rd to m e n o p a u s a l sta t u s an d se ru m p esticid e co n cen t ra t i o n s, th e re su lt s d id n o t a llow fo r a p re c ise asse s sm e n t , d u e t o t h e d ive rs it y o f re su lt s ; o n t h e o t h e r
Tab le 3
Adjuste d O d d s Ratio fo r the e ffe c t o f DDE o n b re ast canc e r in the co lum b ian wo me n.
DDE (ng/ ml) serum levels Cases C o n t ro l s O R*CI 95% O R* *CI 9 5% p- value* * *
Tot al st udy populat ion
0 . 1 0 - 0 . 1 4 3 9 5 5 1 . 0 1 . 0 – 0 . 1 5 - 1 . 9 6 4 5 4 7 1.26 0.72 -2.22 1. 20 0.64- 2.25 0 . 0 9 1 . 9 7 - 1 9 . 2 6 9 5 1 1.82 1.10 -3.10 1.95 1. 10- 3.52 –
P re m e n o p a u s a l
0 . 1 0 - 0 . 1 4 1 5 2 2 1 . 0 1 . 0 – 0 . 1 5 - 2 . 0 6 2 0 2 1 1.25 0. 54 -3.0 1.40 0.55-3.4 3 0 . 0 8 2 . 0 7 - 1 9 . 2 2 5 1 7 1. 84 0.82-4.13 2.46 0.96- 6.3 0 –
P o s t m e n o p a u s a l
0 . 1 0 - 0 . 1 9 2 4 3 3 1 . 0 1 . 0 – 0 . 2 0 - 1 . 9 0 2 5 2 6 1.30 0.60-3.0 1.14 0.50- 2.75 0 . 2 4 0 . 9 1 - 1 9 . 0 4 4 3 4 1.81 0.90 -4.0 1.85 0.84 -4. 05 –
* Matc he d p airid b y ag e .
** Ad juste d fo r b re astfe e d ing at first c hild , familial histo ry o f BC (ye s/ no ), p arity (as c o ntinuo us variab le ), Q ue te le t inde x (Kg / m t2), me no p ausal status (ye s/ no ). *** p -value fo r tre nd (W ilc o xo n rank-sum te st fo r tre n d ) .
n = 306 Tab le 2
Plasma le ve ls o f DD E amo ng case patie nts ad c o ntro ls in the c o lumb ian stud y.
DDE (ng/ ml)* Case patient s M ean (± SD) value M edian value p* *
and controls (n)
E n t i re st udy population
Case p atie nts 1 5 3 3.30 ± 4. 12 1 . 6 0 0 . 0 2 5 C o n t ro l s 1 5 3 2.50 ± 3.60 0 . 9 4 –
M enopausal st at us
P re m e n o p a u s a l
Case p atie nts 6 0 3.02 ± 4.35 1 . 4 6 0 . 0 4 0 C o n t ro l s 6 0 2.1 ± 2. 80 0 . 8 0 –
P o s t m e n o p a u s a l
Case patie nts 9 3 3.45 ± 3.0 1 . 7 2 0 . 2 2 C o n t ro l s 9 3 3.0 ± 4.03 1 . 1 0 –
h a n d , BC ris k d u e t o D DE e xp o s u r e h a s b e e n d e m o n s t ra t e d fo r h o r m o n e - re s p o n s i ve b re a s t ca n c e r s (Ló p e z - Ca r r illo e t a l., 1997). In t h e c u r re n t in ve s t iga t io n , u p o n st ra t ifyin g fo r m e n o p au sa l st at u s, a stro n ge r a sso cia tion wa s s h own b e twee n th e d isea se an d h igh er con cen -t ra -t ion s o f DDE fo r b o -t h p re m e n o p a u s a l a n d p o st m e n o pa u sal wo m en , b u t with ou t re a c h i n g s t a t ist ic a l s ign ific a n c e ; t h e r isk wa s sligh t ly h igh e r in yo u n ge r wo m e n . In a n a ggre g a t e e va lu a t io n o f t h e st u d y gro u p (n = 306), a BC risk of 2 t im es was sh own fo r th e h igh e xp osu re c a t e g o r y (s e e t a b le 3). Th e re a so n t h e va l u e s s u gge st h igh e r e xp o su re in yo u n ge r wo m e n is p ro b a b ly th at we are e va lu a t in g t h e d a m a ge t o u n d i f f e re n t iate d ce lls in yo u n ger wo m e n , wit h g re a t e r e xp o su re d u e t o d e laye d p ri m i p a ri t y, s h o rt er cu m u lat ive b reast -fee d in g, a n d gre a t e r u se of h o rm o n a l co n t r a c e p t i ve s, a d d e d t o t h e p re se n ce o f DDE at ea rlier st a ge s in life (Ke l s e y e t al., 1993; Wo lff et a l.,1993) in a d d itio n t o t h e fa ct t h a t DDE co u ld co n t r ib u te t o an in cre a s e in circu la t in g e st ro ge n s re su ltin g fr o m a su m -m at io n o f e xp o s u re s (b o t h e n d o ge n o u s a n d e n v i ro n m e n tal). In th e case of p ostm en o p au sal wom e n , th e act io n m e ch a n ism of DDE m a y b e m o re re lat e d t o t h e in cre as e in circu la t in g e s-t ro g e n s , a lo n g wis-t h p e ri p h e r al p ro d u cs-t io n o f t h e sam e (Kelsey et al., 1993). We can th u s con -clu d e t ha t th e effect of DDE can p ot en t iate t ra-d it io n a l risk fa ct o rs, e sp e cially in yo u n g e r wo m e n ( Wo lff & West o n , 1997). Ou r resu lt s are co n sist e n t w ith a n d sim ila r to th o se p re s e n t e d b y ot h e r a u t h o rs ( Wo lff e t a l., 1993; Kr ie ge r e t a l., 1994; H u n t e r e t a l., 1997; De wailly e t a l., 1994; Ló p ez - Ca r rillo et a l., 1997). In t h is se n se, 61% o f ou r DDE valu e s we r e b e lo w 5.2 p p b , sim ila r t o t h e le vels re p o rt ed b y Ló p ez - Ca r ri l l o e t al. (1997), a cco rd in g t o wh o m o u t of th e t ot al s e ru m DDE o b se r ved in th e ir su b je cts, 77% (a s c o m p a red t o 46% in Wo lff et a l., 1993) we re b e-l o w t h is figu re , c o rre sp o n d in g in t u rn to t h e secon d q u in tile from th e stu d y b y Krieger e t al. (1994); in t h e la t t e r, o n t h e co n t r a r y, n o n e o f t h e st u d y su b je ct s h a d se r u m DDE va lu e s low-e r t h a n 5.2 p p b . In Co lo m b ia , b o t h t h low-e m low-e a n a n d th e ran ge o f DDE co n cen tra t ion s we re n ot a s h igh a s t h o se r e p o rt e d b y p re vio u s st u d ie s ( Colom b ia m ean for cases wa s 3.30 p p b a s co m -p a red to 11.0 -p -p b in Wo lff e t al. an d 4.75 -p -p b in Me xico ). Ou r re su lt s co n firm t h e h yp ot h e sis ra ise d b y Wo lff e t a l., wit h sim ila r c h a ra c t e ri s-t ics in s-t h e p a s-t s-t e rn of s-t h e re s u ls-t s ( Wo lff e s-t a l., 1993). Th e pesticid e valu es re p o rte d for Co l o m -b ia we re lowe r, -b u t th is is exp la in e d -b y th e fa ct t ha t Co lo m b ian wo m en re flect m o re re cen t e x-p o s u re s, a n d a s h a s b e e n d o cu m e n t e d it is a c o u n t r y w h e re th e u se an d p ro d u ct io n of DDT
-Cad. Saúde Púb lic a, Rio d e Jane iro , 14(Sup. 3):125-132, 1998 cer Research Fou n d ation / Am erican In stitu te f o r
Can cer Re s e ra ch , 1997; Goo d m a n e t a l., 1997). Su ch a sse ssm e n ts are so on t o b e p u b lish e d .
T h e re is so m e c on ce r n a m o n g re s e a rc h e r s t h a t c an ce r c a n a ffe ct b o d y m e t a b o lis m , in -clu d in g in crea sin g t h e b re a k d own o f fat sto re s. Sin ce DDT an d DDE c a n b e st o re d in fa t t y t is-s u e is-s, t h iis-s b re a k d ow n o f fat is-st o re is-s c o u ld re is-s u l t in an in cre ase d rele ase o f DDT o r DDE in to t h e b lo od a n d e ve n to som e d ecre ase in DDE leve l s in a d ip o se t issu e, p e rh a p s d u e t o a co m b in a -tion of ch a n ce an d m o b iliza tio n of en e rgy fro m fa t sto res in cases (Fa lck et a l., 1992). Th is wou ld re s u lt in fa lse ly e le va t e d b lo o d le ve ls o f t h is p e sticid e in BC p a tien ts an d low b rea st fat ty tissu e DDE co n cen tra t i o n s. In t h is se n se, th e Eu -ro p e a n st u d y, co n c lu d e d t h at “Th e low er DDE c o n c e n t ration s observ ed a m on g th e w om en w it h BC m ay be secon dary to disease in cep tion” (Va n’t Ve e r e t a l., 1997:81), a n d in fa ct , t h e y d id n o t s u p p o rt t h e h yp ot he sis t h at DDE in cre ases ri s k of BC in p o s t m e n o p a u s al wo m e n in Eu ro p e, c o n t ra r y t o t h e Ca n a d ian st u d y ( Va n’t Ve e r e t a l., 1997; Ló p e z - Ca r rillo e t a l., 1997). An ot h e r re l e va n t a s p e c t o f t h e Eu r o p e a n s t u d y is t h a t it d id n o t t a ke in t o a cc o u n t t h e d u ra t io n o f b rea st-fee d in g t o a d ju st t he resu lts of th e a sso-cia tio n u n d e r stu d y, an d in re g a rd to h ist o r y of b re a st -fe ed in g, d ifferen t resu lts agre e th a t DDE l e ve ls in m a t e r n a l m ilk d e c re a se d wit h in -c rea sed d u ra tion o f b rea st-fee d in g (Wo lff et a l., 1993; Hu n t e r e t a l., 1997; Gla d e n & Ro g a n , 1995), a lso su p p o rt in g t h e id e a t h a t t h is situ a -t io n w ou ld re d u c e risk of BC ( Wo lff & We s -t o n , 1997; Wo lff e t a l., 1993; H un te r e t a l., 1997).
With re g a rd to t h e m e t h od o logical a sp e ct s of th e cu rren t stu d y, we m igh t th in k th a t an im p e rfe ct m ea su re m e n t o f t h e e xp o su re o f in t er -e st (DDE l-e v-e ls) am o n g a ll wo m -e n -e n r oll-e d in t h e s t u d y w ou ld le a d t o n o n d iffe re n t ial m is -classification a n d a tt en u ate t h e m e asu res of effe ct (ORs fo r b re as t ca n ce r). T h u s, an y la b o ra -t o r y erro r is likely -t o b e n o n d ifferen -t ia l.
Du e t o d iffe re n t e xp o su re s t o e n viro n m e n -t al fac-t o rs in clu d in g ch e m ica l com p o u n d s, d i-e t, an d h igh ly lo cal cu ltu ral asp i-e cts (gi-e n i-e tica l-ly a n d / o r ge o gra p h ic a ll-ly d e t e rm in e d ) t h a t co u ld e xp la in d iffe re n ce s in t h e re s u lt s fro m e x p o s u re t o DD E a n d ris k o f d e ve lo p in g BC, o n e ca n co n clu d e t h a t t h is re la tio n sh ip is su b -ject t o t h e in t erd e p en d en ce o f t he se fa ct ors on in d ivid u a l s u s ce p t ib ilit y t o BC, a n d t h at s u c h i n t e rd ep en d en t fa cto rs h a ve st ill n ot b ee n fu lly i n c o r p o ra t e d in t o re s e a rc h . Evid e n ce fo r t h is w a s t h e a s so c ia t io n o b se r ve d b e t we e n p e st i-cid e exp o su re a n d BC wh e n co m p a rin g e t h n ic g ro u p s in t h e st u d y b y Kr ie ge r e t a l. (1994), a resu lt th a t h a d n ot b e en o b se r ve d wh e n eva l u -a t in g t h e gro u p -as -a wh o le ( Wo lff &-amp; We s t o n , 1997; Krie ge r e t al., 1994). Re ce n t st u d ie s p ro -vid e e -vid e n c e t h a t t h e syn e rgis t ic a c t ivit y o f m an y c o m m o n p e s t icid e s m a y b e sign ifica n t ( Wo lff & We st o n , 1997; Ma cLa ch la n & Arn o l d , 1996; Allen et al., 1997; Wolff & Lan d rigan , 1 9 9 4 ) . In ad d it io n , in t e ra ct io n s o f c h e m ica ls in t h e b od y a re n ot we ll u n d e rst o od . Sim p le a d d it ive m o d e ls m a y a p p r oxim a t e b iolo gica l e ffe ct s a t o n e m om en t o f exp osu re, b u t su ch m od els c a n -n ot t ake i-n t o accou -n t re l a t i ve rat e s o f m e t a b o-lism , su sc ep t ib ilit y d u e t o in h er it e d m e ta b o lic c a p a c i t y, su s c e p t ib ilit y d u e t o b re a s t e p it h e -lial d e ve lo p m e n t , o r syn ergistic in te ract ion s o f ch em ica ls ( Wo lff & We st o n , 1997; Ma c L a c h l a n & Arn old , 1996; Allen et a l., 1997; Ha n s e y, 1 9 9 4 ) . Be c a u s e o f t h e a b se n ce o f st u d ie s o n wo m e n w it h kn own e xp osu re s t o DDT a n d th e in co n -s i-st e n t re -su lt -s in t h e -s t u d ie -s e xa m in in g le ve l -s of DDT/ DDE in BC p a t ie n ts a n d wo m e n wit h -o u t t h e d is e a se , a n d t akin g in t -o a c c-o u n t a ll t h e se in te rre l a t i o n s h i p s, t h e re is cu r re n t ly n ot e n o u gh e vid e n ce t o a ffirm t h a t D DT o r DD E d oe s o r d o es n o t ca u se BC in h u m a n s. Howe v-e r, v-e xp osu rv-e to org a n o c h l o rin v-e s in La t in Am v- erica re q u i re s fu rt h e r e va lu a t io n in ord e r to d e -t e r m in e e s p e cia lly -t h e p o -t e n -t ia l d a m a ge -t o w o m e n’s h e a lt h . En f o rc e m e n t o f t h e cu r re n t le gisla tio n on p e st icid e u s e sh o u ld t h u s b e s t re n g t h e n e d .
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